Maintenance Of Cellular Homeostasis Research Articles

14-3-3 Protein-Protein Interactions: From Mechanistic Understanding to their Small-molecule Stabilization.

Protein-protein interactions (PPIs) are of utmost importance for maintenance of cellular homeostasis. Herein, a central role can be found for 14-3-3 proteins. These hub-proteins are known to bind hundreds of interaction partners, thereby regulating their activity, localization, and/or stabilization. Due to their ability to bind a large variety of client proteins, studies of 14-3-3 protein complexes flourished over the last decades, aiming to gain greater molecular understanding of these complexes and their role in health and disease. Because of their crucial role within the cell, 14-3-3 protein complexes are recognized as highly interesting therapeutic targets, encouraging the discovery of small molecule modulators of these PPIs. We discuss various examples of 14-3-3-mediated regulation of its binding partners on a mechanistic level, highlighting the versatile and multi-functional role of 14-3-3 within the cell. Furthermore, an overview is given on the development of stabilizers of 14-3-3 protein complexes, from initially used natural products to fragment-based approaches. These studies show the potential of 14-3-3 PPI stabilizers as novel agents in drug discovery and as tool compounds to gain greater molecular understandings of the role of 14-3-3-based protein regulation.

The Emerging Role of Ubiquitin-Specific Protease 36 (USP36) in Cancer and Beyond.

The balance between ubiquitination and deubiquitination is instrumental in the regulation of protein stability and maintenance of cellular homeostasis. The deubiquitinating enzyme, ubiquitin-specific protease 36 (USP36), a member of the USP family, plays a crucial role in this dynamic equilibrium by hydrolyzing and removing ubiquitin chains from target proteins and facilitating their proteasome-dependent degradation. The multifaceted functions of USP36 have been implicated in various disease processes, including cancer, infections, and inflammation, via the modulation of numerous cellular events, including gene transcription regulation, cell cycle regulation, immune responses, signal transduction, tumor growth, and inflammatory processes. The objective of this review is to provide a comprehensive summary of the current state of research on the roles of USP36 in different pathological conditions. By synthesizing the findings from previous studies, we have aimed to increase our understanding of the mechanisms underlying these diseases and identify potential therapeutic targets for their treatment.

Curcumin and its anti-colorectal cancer potential: From mechanisms of action to autophagy.

Colorectal cancer (CRC) development and progression, one of the most common cancers globally, is supported by specific mechanisms to escape cell death despite chemotherapy, including cellular autophagy. Autophagy is an evolutionarily highly conserved degradation pathway involved in a variety of cellular processes, such as the maintenance of cellular homeostasis and clearance of foreign bodies, and its imbalance is associated with many diseases. However, the role of autophagy in CRC progression remains controversial, as it has a dual function, affecting either cell death or survival, and is associated with cellular senescence in tumor therapy. Indeed, numerous data have been presented that autophagy in cancers serves as an alternative to cell apoptosis when the latter is ineffective or in apoptosis-resistant cells, which is why it is also referred to as programmed cell death type II. Curcumin, one of the active constituents of Curcuma longa, has great potential to combat CRC by influencing various cellular signaling pathways and epigenetic regulation in a safe and cost-effective approach. This review discusses the efficacy of curcumin against CRC in vitro and in vivo, particularly its modulation of autophagy and apoptosis in various cellular pathways. While clinical studies have assessed the potential of curcumin in cancer prevention and treatment, none have specifically examined its role in autophagy. Nonetheless, we offer an overview of potential correlations to support the use of this polyphenol as a prophylactic or co-therapeutic agent in CRC.

Toxicity assessment of perfluorooctane sulfonate on regenerating planarian Dugesia japonica

ABSTRACT As a common environmental contaminant, perfluorooctane sulfonate (PFOS) can be detected in environmental media, plants, animal organs, and humans. PFOS has multiple toxic effects on neural regeneration and development in planarians, zebrafish, and other animals, but the toxic effects exerted on the maintenance of cellular homeostasis and the expression of neuron-related genes during planarian regeneration remain unclear. In this study, planarians were cut at the post-auricle level and then exposed to PFOS for different lengths of time. It was found that PFOS exposure promoted the expression of DjpiwiA, a specific marker gene of neoblasts, which was related to regeneration and the maintenance of homeostasis in planarians. High PFOS exposure inhibited the proliferation of regenerating planarian neoblasts, and there was also an effect on apoptosis in regenerating planarians after PFOS exposure. The results suggested that PFOS exposure in regenerating planarians resulted in a reduction in the density of brain ganglia and inconspicuous brain branching and altered neuronal gene expression in the nervous system. The findings of this study suggest that PFOS has multiple toxic effects on the planarian regeneration and provide a basis for uncovering the toxic effects of PFOS on stem cell proliferation, apoptosis, and the CNS.

Identification of autophagy receptors for the Crohn's disease-associated adherent-invasive Escherichia coli.

Crohn's disease (CD) is a chronic inflammatory bowel disease, of which the etiology involves genetic, environmental and microbial factors. Adherent-invasive Escherichia coli (AIEC) and polymorphisms in autophagy-related genes have been implicated in CD etiology. Autophagy is a key process for the maintenance of cellular homeostasis, which allows the degradation of damaged cytoplasmic components and pathogens via lysosome. We have shown that a functional autophagy is necessary for AIEC clearance. Here, we aimed at identifying the autophagy receptor(s) responsible to target AIEC to autophagy for degradation. The levels of autophagy receptors p62, NDP52, NBR1, TAX1BP1 and Optineurin were knocked down in human intestinal epithelial cells T84 using siRNAs. The NDP52 knock-out (KO) and p62 KO HeLa cells, as well as NDP52 KO HeLa cells expressing the wild-type NDP52 or the mutated NDP52Val248Ala protein were used. We showed that, among the tested autophagy receptors (p62, NDP52, NBR1, TAX1BP1 and Optineurin), diminished expression of p62 or NDP52 increased the number of the clinical AIEC LF82 strain inside epithelial cells. This was associated with increased pro-inflammatory cytokine production. Moreover, p62 or NDP52 directly colocalized with AIEC LF82 and LC3, an autophagy marker. As the NDP52Val248Ala polymorphism has been associated with increased CD susceptibility, we investigated its impact on AIEC control. However, in HeLa cell and under our experimental condition, no effect of this polymorphism neither on AIEC LF82 intracellular number nor on pro-inflammatory cytokine production was observed. Together, our results suggest that p62 and NDP52 act as autophagy receptors for AIEC recognition, controlling AIEC intracellular replication and inflammation.

Poly(ADP-Ribose) Polymerases-Inhibitor Talazoparib Inhibits Muscle Atrophy and Fatty Infiltration in a Tendon Release Infraspinatus Sheep Model: A Pilot Study.

Structural muscle changes, including muscle atrophy and fatty infiltration, follow rotator cuff tendon tear and are associated with a high repair failure rate. Despite extensive research efforts, no pharmacological therapy is available to successfully prevent both muscle atrophy and fatty infiltration after tenotomy of tendomuscular unit without surgical repair. Poly(ADP-ribose) polymerases (PARPs) are identified as a key transcription factors involved in the maintenance of cellular homeostasis. PARP inhibitors have been shown to influence muscle degeneration, including mitochondrial hemostasis, oxidative stress, inflammation and metabolic activity, and reduced degenerative changes in a knockout mouse model. Tenotomized infraspinatus were assessed for muscle degeneration for 16 weeks using a Swiss Alpine sheep model (n = 6). All sheep received daily oral administration of 0.5 mg Talazoparib. Due to animal ethics, the treatment group was compared with three different controls from prior studies of our institution. To mitigate potential batch heterogeneity, PARP-I was evaluated in comparison with three distinct control groups (n = 6 per control group) using the same protocol without treatment. The control sheep were treated with an identical study protocol without Talazoparib treatment. Muscle atrophy and fatty infiltration were evaluated at 0, 6 and 16 weeks post-tenotomy using DIXON-MRI. The controls and PARP-I showed a significant (control p < 0.001, PARP-I p = 0.01) decrease in muscle volume after 6 weeks. However, significantly less (p = 0.01) atrophy was observed in PARP-I after 6 weeks (control 1: 76.6 ± 8.7%; control 2: 80.3 ± 9.3%, control 3: 73.8 ± 6.7% vs. PARP-I: 90.8 ± 5.1% of the original volume) and 16 weeks (control 1: 75.7 ± 9.9; control 2: 74.2 ± 5.6%; control 3: 75.3 ± 7.4% vs. PARP-I 93.3 ± 10.6% of the original volume). All experimental groups exhibited a statistically significant (p < 0.001) augmentation in fatty infiltration following a 16-week period when compared to the initial timepoint. However, the PARP-I showed significantly less fatty infiltration (p < 0.003) compared to all controls (control 1: 55.6 ± 6.7%, control 2: 53.4 ± 9.4%, control 3: 52.0 ± 12.8% vs. PARP-I: 33.5 ± 8.4%). Finally, a significantly (p < 0.04) higher proportion and size of fast myosin heavy chain-II fiber type was observed in the treatment group. This study shows that PARP-inhibition with Talazoparib inhibits the progression of both muscle atrophy and fatty infiltration over 16 weeks in retracted sheep musculotendinous units.

SGLT2-Inhibitors and Kidney Protection: Mechanisms Beyond Tubulo-Glomerular Feedback.

Sodium-glucose cotransporter 2 (SGLT2)-inhibitors reduce the risk for kidney failure and are a key component of guideline-directed therapy for chronic kidney disease. While SGLT2-inhibitors' ability to activate tubulo-glomerular feedback and reduce hyperfiltration-mediated kidney injury is considered to be the central mechanism for kidney protection, recent data from experimental studies raises questions on the primacy of this mechanism. This review examines SGLT2-inhibitors' role in tubulo-glomerular feedback and summarizes emerging evidence on following of SGLT2-inhibitors' other putative mechanisms for kidney protection: optimization of kidney's energy substrate utilization and delivery, regulation of autophagy and maintenance of cellular homeostasis, attenuation of sympathetic hyperactivity, and improvement in vascular health and microvascular function. It is imperative to examine the impact of SGLT2 inhibition on these different physiologic processes to help our understanding of mechanisms underpinning kidney protection with this important class of drugs.

Oxidative stress status and antioxidative responses in neonate versus adult Daphnia magna exposed to polystyrene leachate

Abstract Objective Plastic pollution, particularly polystyrene, significantly threatens aquatic ecosystems worldwide. Furthermore, plastic leachates have been documented to be detrimental to some aquatic organisms; however, understanding the toxicity mechanism remains limited. This study aimed to investigate the ecotoxicological effects of polystyrene leachate on neonate and adult Daphnia magna, a keystone species in freshwater ecosystems. Methods The effects of the leachate were studied by employing the novel technique of separating daphnids from the polystyrene microplastic fragments via dialysis tubing, which was prepared 24 and 72 h before organism exposure. Acute toxicity was assessed as effects on organism mobility, oxidative stress (reactive oxygen species), antioxidative enzyme responses (superoxide dismutase and catalase), as well as the effects on the biotransformation enzyme glutathione S-transferase’s activity. Results Under the experimental conditions, the mobility and oxidative status of the daphnids were unaffected, irrespective of the organisms’ age or leaching time. In adults exposed for 24 h, the antioxidant defense enzyme activities were elevated, contributing to cellular homeostasis maintenance. However, the catalase activity was reduced for neonates and adults exposed to the prolonged pre-leached treatment, thus making them less capable of retaining homeostasis when exposed to toxicant mixtures. Conclusion This study highlights the vulnerability of D. magna to polystyrene leachate and underscores the need for continued research on the ecotoxicological effects of plastic pollution in aquatic ecosystems. Findings from this investigation contribute to understanding the ecological consequences of plastic pollution, which can inform mitigation strategies and policy decisions to preserve the health and integrity of freshwater ecosystems.

Abstract 408: NEK1 phosphorylation modulates ERCC6 in transcription coupled nucleotide excision repair with implications for prostate cancer

Abstract NER operates through two distinct pathways: global genome repair (GGR) and transcription-coupled repair (TC-NER). TC-NER, as its name suggests, is specifically dedicated to rectifying lesions that obstruct the progression of RNA polymerase during active transcription. This process is imperative for the maintenance of cellular homeostasis, as lesions encountered by the transcription machinery can lead to stalling, erroneous transcription, and ultimately, deleterious cellular outcomes. At the heart of the TC-NER pathway lies ERCC6, a helicase orchestrating the repair of DNA lesions within transcribed regions of the genome. ERCC6 (AKA CS-B) plays a pivotal role in detecting and coordinating the repair of transcription-blocking lesions and has been implicated in a plethora of cellular processes underscoring its multifaceted nature and its broader impact on genome stability and cellular health, as exemplified by the severity of syndromes in individuals with loss-of-function mutations. In the US, compared to Caucasians (CC), AA are at higher risk for developing PCa and have more aggressive disease that is refractory to treatment, to some extent explained by genetic differences in some cases attributed to alterations of their “Repairome”. GWAS revealed that, unlike CC, 89% of AA-PCa have at least one mutation in NER pathway genes. A defect in ERCC6 activity, either through reduced expression or mutation (e.g., M1097V found frequently in AA) may result in impaired TC-NER. This may be compounded by aging or obesity-related oxidative stress, resulting in progressive accumulation of damaged bases (e.g., 8-OG) and consequent (cancer-propensity) mutations, the correction of which involves BER or NER. This was investigated in part with PCa cell lines engineered via CRISPR-SDM to carry that particular genomic mutation, by studying their sensitivity to UV and the efficiency of removal of CPDs in vivo. In addition, we have begun investigation of its function in the variants (engineered and naturally found in PCa. Lines) in vitro, after IP from cells, by studying its intrinsic ATPase activity. We have also identified the kinase NEK1 as an important novel interactor and regulator of ERCC6. We previously identified NEK1 as being an early regulator of the adaptive response of PCa cells to ADT. Citation Format: Oluwatobi M. Ogundepo, Arrigo De Benedetti. NEK1 phosphorylation modulates ERCC6 in transcription coupled nucleotide excision repair with implications for prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 408.

Abstract 3163: (Phospho)proteomic analysis reveals vulnerabilities in refractory metastatic colorectal cancer

Abstract Proteomic networks are crucial for cellular homeostasis maintenance and, indeed, their aberrant regulation is implicated in cancer development and progression. Understanding alterations underlying these pathways, provides a way to design therapeutic interventions in human cancer. Improvements in mass spectrometry analysis have unlocked our potential to unveil cancer vulnerabilities. Here, we performed (phospho)proteomic analysis and ex-vivo drug testing on a cohort of refractory metastatic colorectal cancer (mCRC) tissues and matched patients-Derived Organoids (PDO) to identify new putative druggable biomarkers. The comparison between the proteome and phosphoproteome of 10 mCRCs tissues with their matched PDOs normalized to a pool of 6 colon mucosa tissues highlighted a strong overall correlation (R= 0.57 and R=0.6, respectively) suggesting a good level of similarity. Applying GSEA on our proteomic dataset, we identified up-regulation in MYC, cell cycle and MTORC1 signaling pathways in mCRC tissues and PDO, while kinase enrichment analysis highlighted an increase in Casein Kinase II (CKII) activity, an important cell cycle regulator. Our ex-vivo experiments showed that silmitasertib-mediated CKII inhibition reduced the cell viability in our PDO models, but with an overall modest effect. Analysis revealed that, even though not statistically significant, high Wnt signaling score correlated with an higher resistance to silmitasertib treatment (R=0.61; p=0.08). Previous works highlighted that MAPK activity is increased after silmitasertib treatment and responsible for resistance mechanisms to CKII inhibition. Strikingly, the combined trametinib-mediated MEK blockade and CKII blockade resulted in a synergistic interaction leading to enhanced antitumor activity, especially in PDO harboring high Wnt (R=0.74; p=0.022) and cell cycle (R=0.69; p=0.04) pathway activity. Moreover, the combined treatment strongly reduced S6 activity and RAPTOR expression, overcoming the significant effect exerted by the single agents. Surprisingly, none of them altered baseline MAPK activity, suggesting that silmitasertib and trametinib synergize their activity via inactivating the MTORC1-S6 axis in an ERK-independent manner. We are currently integrating genomic and transcriptomic data to better characterize the observed drug synergy. Taken together, our findings propose the silmitasertib and trametinib combination as a new therapeutic opportunity for refractory mCRC patients and strengthen the use of PDO as a suitable model for drug screening. Citation Format: Mattia Marinucci, Gina Faye Boot, Lara Zaidi, Cinzia Esposito, Mairene Coto Llerena, Savas Soysal, Otto Kolmar, Charlotte K Y Ng, Salvatore Piscuoglio. (Phospho)proteomic analysis reveals vulnerabilities in refractory metastatic colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3163.

POLR3A-mutated Wiedemann-Rautenstrauch fibroblasts display differential profile of intron retention and expression of TP53 isoforms

BACKGROUND: Wiedemann-Rautenstrauch Syndrome (WRS) is a neonatal progeroid syndrome for which biallelic pathogenic variants in RNA polymerase III subunit A (POLR3A) have recently been described. POLR3 is a 17 subunits protein complex responsible for the transcription of short RNAs including all the transfer RNAs (tRNAs), the 5 S subunit of ribosomal RNA, the short nuclear RNA U6, among other regulatory RNAs. OBJECTIVE: We aim to evaluate the impact of POLR3A pathogenic variants on the relative expression of the short nuclear RNA U6 and on the differential profile of intron retention RNA U6, p53 isoforms and in fibroblasts derived from patients with WRS and control fibroblasts. METHODS: RNA was extracted by the TRIzol method; intron retention analysis was performed by using IRFinder from an mRNA sequencing (RNA-Seq) platform; P53 isoforms, short nuclear RNA U6 and additional genes related to cell senescence were measured by RT-PCR. RESULTS: No significant differences were found in the percentage of intron retention (control: 7.8%, WRS1 : 6.3%and WRS2 : 8.14%). Genes showing higher intron retention profile in both groups were mainly related to RNA binding pathways, cell cycle regulation, positive regulation of transcription, positive regulation of inflammatory pathways, negative regulation of apoptosis, RNA transcription, mitochondria, and regulation of translation initiation. However, in WRS fibroblasts the genes with more intron retention were those related to the immune response and mitochondrial function; while in control those related to the response to oxidative stress had the most introns retained. WRS1 showed higher expression of short nuclear RNA U6 compared to control and WRS2; while both WRS cells showed higher expression of p53β and lower percentage of Δ133p63α, consistent with a higher expression of the cellular senescence markers p16 and p21. CONCLUSIONS: These results demonstrated the important role of POLR3A in the maintenance of cellular homeostasis and highlight its potential role in cell senescence in WRS.

Disrupting the SKN-1 homeostat: mechanistic insights and phenotypic outcomes.

The mechanisms that govern maintenance of cellular homeostasis are crucial to the lifespan and healthspan of all living systems. As an organism ages, there is a gradual decline in cellular homeostasis that leads to senescence and death. As an organism lives into advanced age, the cells within will attempt to abate age-related decline by enhancing the activity of cellular stress pathways. The regulation of cellular stress responses by transcription factors SKN-1/Nrf2 is a well characterized pathway in which cellular stress, particularly xenobiotic stress, is abated by SKN-1/Nrf2-mediated transcriptional activation of the Phase II detoxification pathway. However, SKN-1/Nrf2 also regulates a multitude of other processes including development, pathogenic stress responses, proteostasis, and lipid metabolism. While this process is typically tightly regulated, constitutive activation of SKN-1/Nrf2 is detrimental to organismal health, this raises interesting questions surrounding the tradeoff between SKN-1/Nrf2 cryoprotection and cellular health and the ability of cells to deactivate stress response pathways post stress. Recent work has determined that transcriptional programs of SKN-1 can be redirected or suppressed to abate negative health outcomes of constitutive activation. Here we will detail the mechanisms by which SKN-1 is controlled, which are important for our understanding of SKN-1/Nrf2 cytoprotection across the lifespan.

Hydrogels for ameliorating osteoarthritis: Mechanical modulation, anti‐inflammation, and regeneration

AbstractOsteoarthritis (OA) is a chronic and degenerative disease with limited clinical options for effective suppression. Recently, significant endeavors have been explored to reveal its pathogenesis and develop treatments against OA. Hydrogels, designed with a striking resemblance to the extracellular matrix, offer a biomimetic interaction with biological tissues, presenting a promising avenue for OA amelioration. As a result, biocompatible hydrogels have been erected incorporating on‐demand bioactivities to optimize the intra‐articular microenvironment, thereby alleviating OA symptoms and fostering the eventual regeneration of articular joints. This review highlights the collaborative objectives underlying the establishment of this tissue microenvironment, encompassing mechanical modulation, anti‐inflammation, and tissue regeneration. Specifically, we consolidate recent advances in hydrogel‐based biomaterials, serving as the tissue engineering scaffolds to replicate the lubrication properties of natural joints or the bioactive agent‐loaded vehicles to combat localized inflammation. Additionally, hydrogels function as cell scaffolds to facilitate the maintenance of cellular homeostasis and contribute to the advancement of cartilage regeneration. Finally, this review outlines the prospective directions for hydrogel‐mediated OA therapies.

Cilia Provide a Platform for the Generation, Regulated Secretion, and Reception of Peptidergic Signals.

Cilia are microtubule-based cellular projections that act as motile, sensory, and secretory organelles. These structures receive information from the environment and transmit downstream signals to the cell body. Cilia also release vesicular ectosomes that bud from the ciliary membrane and carry an array of bioactive enzymes and peptide products. Peptidergic signals represent an ancient mode of intercellular communication, and in metazoans are involved in the maintenance of cellular homeostasis and various other physiological processes and responses. Numerous peptide receptors, subtilisin-like proteases, the peptide-amidating enzyme, and bioactive amidated peptide products have been localized to these organelles. In this review, we detail how cilia serve as specialized signaling organelles and act as a platform for the regulated processing and secretion of peptidergic signals. We especially focus on the processing and trafficking pathways by which a peptide precursor from the green alga Chlamydomonas reinhardtii is converted into an amidated bioactive product-a chemotactic modulator-and released from cilia in ectosomes. Biochemical dissection of this complex ciliary secretory pathway provides a paradigm for understanding cilia-based peptidergic signaling in mammals and other eukaryotes.

Orchestrating Cellular Balance: ncRNAs and RNA Interactions at the Dominant of Autophagy Regulation in Cancer.

Autophagy, a complex and highly regulated cellular process, is critical for the maintenance of cellular homeostasis by lysosomal degradation of cellular debris, intracellular pathogens, and dysfunctional organelles. It has become an interesting and attractive topic in cancer because of its dual role as a tumor suppressor and cell survival mechanism. As a highly conserved pathway, autophagy is strictly regulated by diverse non-coding RNAs (ncRNAs), ranging from short and flexible miRNAs to lncRNAs and even circRNAs, which largely contribute to autophagy regulatory networks via complex RNA interactions. The potential roles of RNA interactions during autophagy, especially in cancer procession and further anticancer treatment, will aid our understanding of related RNAs in autophagy in tumorigenesis and cancer treatment. Herein, we mainly summarized autophagy-related mRNAs and ncRNAs, also providing RNA-RNA interactions and their potential roles in cancer prognosis, which may deepen our understanding of the relationships between various RNAs during autophagy and provide new insights into autophagy-related therapeutic strategies in personalized medicine.

Activation of Ca2+ phosphatase Calcineurin regulates Parkin translocation to mitochondria and mitophagy in flies

Selective removal of dysfunctional mitochondria via autophagy is crucial for the maintenance of cellular homeostasis. This event is initiated by the translocation of the E3 ubiquitin ligase Parkin to damaged mitochondria, and it requires the Serine/Threonine-protein kinase PINK1. In a coordinated set of events, PINK1 operates upstream of Parkin in a linear pathway that leads to the phosphorylation of Parkin, Ubiquitin, and Parkin mitochondrial substrates, to promote ubiquitination of outer mitochondrial membrane proteins. Ubiquitin-decorated mitochondria are selectively recruiting autophagy receptors, which are required to terminate the organelle via autophagy. In this work, we show a previously uncharacterized molecular pathway that correlates the activation of the Ca2+-dependent phosphatase Calcineurin to Parkin translocation and Parkin-dependent mitophagy. Calcineurin downregulation or genetic inhibition prevents Parkin translocation to CCCP-treated mitochondria and impairs stress-induced mitophagy, whereas Calcineurin activation promotes Parkin mitochondrial recruitment and basal mitophagy. Calcineurin interacts with Parkin, and promotes Parkin translocation in the absence of PINK1, but requires PINK1 expression to execute mitophagy in MEF cells. Genetic activation of Calcineurin in vivo boosts basal mitophagy in neurons and corrects locomotor dysfunction and mitochondrial respiratory defects of a Drosophila model of impaired mitochondrial functions. Our study identifies Calcineurin as a novel key player in the regulation of Parkin translocation and mitophagy.

Herbal Drugs Inducing Autophagy for the Management of Cancer: Mechanism and Utilization.

When compared to chemical medicines, herbal medicines have the greatest therapeutic benefit while having fewer harmful side effects. Many different components in herbs have an anticancer impact, but the exact mechanism of how they work is unknown. Some herbal medicines have even been shown to trigger autophagy, a process that has shown promise as a potential cancer treatment. In the past ten years, autophagy has come to be recognised as a crucial mechanism in the maintenance of cellular homeostasis, which has led to the discovery of its implications in the pathology of the majority of cellular environments as well as human disorders. Autophagy is a catabolic process that is used by cells to maintain their homeostasis. This process involves the degradation of misfolded, damaged, and excessive proteins, as well as nonfunctional organelles, foreign pathogens, and other cellular components. Autophagy is a highly conserved process. In this review article, several naturally occurring chemicals are discussed. These compounds offer excellent prospects for autophagy inducers, which are substances that can hasten the death of cells when used as a complementary or alternative treatment for cancer. It requires additional exploration in preclinical and clinical investigations, notwithstanding recent advances in therapeutic medications or agents of natural products in numerous cancers. These advancements have been made despite the need for further investigation.

Targeting the Ubiquitin-Proteasome System and Recent Advances in Cancer Therapy.

Ubiquitination is a reversible post-translational modification based on the chemical addition of ubiquitin to proteins with regulatory effects on various signaling pathways. Ubiquitination can alter the molecular functions of tagged substrates with respect to protein turnover, biological activity, subcellular localization or protein-protein interaction. As a result, a wide variety of cellular processes are under ubiquitination-mediated control, contributing to the maintenance of cellular homeostasis. It follows that the dysregulation of ubiquitination reactions plays a relevant role in the pathogenic states of human diseases such as neurodegenerative diseases, immune-related pathologies and cancer. In recent decades, the enzymes of the ubiquitin-proteasome system (UPS), including E3 ubiquitin ligases and deubiquitinases (DUBs), have attracted attention as novel druggable targets for the development of new anticancer therapeutic approaches. This perspective article summarizes the peculiarities shared by the enzymes involved in the ubiquitination reaction which, when deregulated, can lead to tumorigenesis. Accordingly, an overview of the main pharmacological interventions based on targeting the UPS that are in clinical use or still in clinical trials is provided, also highlighting the limitations of the therapeutic efficacy of these approaches. Therefore, various attempts to circumvent drug resistance and side effects as well as UPS-related emerging technologies in anticancer therapeutics are discussed.

Dual-specificity phosphatase 1 inhibits Singapore grouper iridovirus replication via regulating apoptosis in Epinephelus coioides

The dual-specificity phosphatase (DUSP) family plays key roles in the maintenance of cellular homeostasis and apoptosis etc. In this study, the DUSP member DUSP1 of Epinephelus coioides was characterized: the length was 2371 bp including 281 bp 5′ UTR, 911 bp 3′ UTR, and a 1125 bp open reading frame encoding 374 amino acids. E. coioides DUSP1 has two conserved domains, a ROHD and DSPc along with a p38 MAPK phosphorylation site, localized at Ser308. E. coioides DUSP1 mRNA can be detected in all of the tissues examined, and the subcellular localization showed that DUSP1 was mainly distributed in the nucleus. Singapore grouper iridovirus (SGIV) infection could induce the differential expression of E. coioides DUSP1. Overexpression of DUSP1 could inhibit SGIV-induced cytopathic effect (CPE), the expressions of SGIV key genes, and the viral titers. Overexpression of DUSP1 could also regulate SGIV-induced apoptosis, and the expression of apoptosis-related factor caspase 3. The results would be helpful to further study the role of DUSP1 in viral infection.

Viruses and autophagy: bend, but don't break.

Autophagy is a constitutive cellular process of degradation required to maintain homeostasis and turn over spent organelles and aggregated proteins. For some viruses, the process can be antiviral, degrading viral proteins or virions themselves. For many other viruses, the induction of the autophagic process provides a benefit and promotes viral replication. In this Review, we survey the roles that the autophagic pathway plays in the replication of viruses. Most viruses that benefit from autophagic induction block autophagic degradation, which is a 'bend, but don't break' strategy initiating but limiting a potentially antiviral response. In almost all cases, it is other effects of the redirected autophagic machinery that benefit these viruses. This rapid mechanism to generate small double-membraned vesicles can be usurped to shape membranes for viral genome replication and virion maturation. However, data suggest that autophagic maintenance of cellular homeostasis is crucial for the initiation of infection, as viruses have evolved to replicate in normal, healthy cells. Inhibition of autophagic degradation is important once infection has initiated. Although true degradative autophagy is probably a negative for most viruses, initiating nondegradative autophagic membranes benefits a wide variety of viruses.